BTZ-Derived Benzisothiazolinones with In Vitro Activity against Mycobacterium tuberculosis

Abstract

8-Nitro-1,3-benzothiazin-4-ones (BTZs) are known as potent antitubercular agents. BTZ043 as one of the most advanced compounds has reached clinical trials. The putative oxidation products of BTZ043, namely, the corresponding BTZ sulfoxide and sulfone, were reported in this journal (Tiwari et al. ACS Med. Chem Lett. 2015, 6, 128-133). The molecular structures were later revised to the constitutionally isomeric benzisothiazolone and its 1-oxide, respectively. Here, we report two BTZ043-derived benzisothiazolinones (BITs) with in vitro activity against mycobacteria. The constitutionally isomeric O-acyl benzisothiazol-3-ols, in contrast, show little or no antimycobacterial activity in vitro. The structures of the four compounds were investigated by X-ray crystallography and NMR spectroscopy. Molecular covalent docking of the new compounds to Mycobacerium tuberculosis decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) suggests that the active BITs exert antimycobacterial activity through inhibition of DprE1 like BTZs.

Scheme 1. Reaction of BTZs 1a and 1b (BTZ043) with m-Chloroperoxybenzoic Acid (mCPBA): Putative Chemical Structures “BTZ-SO” and “BTZ-SO₂” Assigned by Tiwari et al. and Corresponding Revised Chemical Structures Reported by Eckhardt et al.

Scheme 2. Syntheses of N-Acyl BITs 4a and 4b and O-Acyl Benzisothiazolols 5a and 5b

Reagents and conditions: (i) CuI, 1,10-phenanthroline, sulfur, K₂CO₃, DMF, 110 °C, overnight; (ii) piperidine-1-carbonyl chloride (a) or (S)-2-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carbonyl chloride (b), pyridine, CH₂Cl₂, rt, 24 h.

Figure 1

Crystal structure of 4a·0.25 H₂O. (a) Asymmetric unit. Carbon-bound hydrogen atoms are omitted for clarity. (b) Structure overlay (benzene rings) of the three crystallographically unique molecules (pink, blue, gray). (c) Displacement ellipsoid plot (50% probability) of molecule 1. Rotational disorder of the trifluoromethyl group and positional disorder of a water hydrogen atom are not shown for clarity. Color scheme: C, gray; H, white; N, blue; O, red; S, yellow.

Figure 2

Chemical diagrams and structure overlay (benzene rings) of DFT-optimized molecular structures of 4a and 4b (orange) and the BTO constitutional isomers 6a(32) and 6b (green). Hydrogen atoms are omitted for clarity.

Figure 3

Asymmetric unit of the crystal structure of 4b. Displacement ellipsoid plots are drawn at the 50% probability level. Rotational disorder of the trifluoromethyl groups is omitted for clarity. Color scheme: C, gray; H, white; N, blue; O, red; S, yellow.

Figure 4

Section of the crystal structure of 5a, showing two molecules related by a crystallographic inversion center. Displacement ellipsoids are drawn at the 50% probability level. The crystal structure was refined with aspherical scattering factors using NoSpherA2. Color scheme: C, gray; H, white; N, blue; O, red; S, yellow.

Figure 5

Asymmetric unit of the crystal structure of 5b. Displacement ellipsoids are drawn at the 50% probability level. Color scheme: C, gray; H, white; N, blue; O, red; S, yellow.

Figure 6

Aliphatic region of the ¹³C NMR spectra of 4a, 5a, 4b, and 5b in CDCl₃ at room temperature (the full spectra are shown in the Supporting Information).

Figure 7

Highest ranked molecular covalent docking solution of 4a to M. tuberculosis DprE1.

Figure 8

Highest ranked molecular docking solutions for (A) 4a, (B) 4b, (C) 5a, and (D) 5b (docked to 6HEZ.B; flexible side chains for Lys134, Trp230, Val365, Leu363, Lys418; toggled water molecules; solution number as in Table S2).